Mutations

PSEN1 V261I

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73664750 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to ATT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in an individual diagnosed with familial AD (Miravalle et al., 2005). Symptoms emerged at age 48 and death occurred at 55. The patient was homozygous for the APOE3 allele and had no mutations in exons 16 and 17 of the APP gene. Although the disease was described as familial, no information was reported for family members.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathology was consistent with AD, including neuritic plaques, diffuse amyloid deposits, and cotton wool plaques. The latter were the most abundant amyloid species, with widespread distribution in the neocortex, caudate nucleus, putamen, thalamus, amygdala, hippocampus, parahippocampus, and midbrain. The predominant Aβ species in cotton wool plaques were amino-terminally truncated Aβ42 and Aβ43 peptides, with no detectable Aβ40. A similar Aβ composition was observed in the diffuse amyloid deposits of the cerebellum. In contrast, in the amyloid deposits associated with parenchymal and leptomeningeal vessels, Aβ40 was the predominant species.

Biological Effect
The biological effect of this variant is unknown, but several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). These authors classified the variant as likely pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

Last Updated: 10 Sep 2021

Comments

  1. This interesting paper corroborates the new concept that N-terminal truncated Aβ42 species are the seeds of amyloidosis, and a nice target for the vaccination approach.

    References:

    . Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach. J Neurochem. 2003 Jun;85(6):1581-91. PubMed.

    View all comments by Andre Delacourte

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References

Paper Citations

  1. . Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques. Biochemistry. 2005 Aug 16;44(32):10810-21. PubMed.
  2. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
  3. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques. Biochemistry. 2005 Aug 16;44(32):10810-21. PubMed.

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